ArticleCancer research2017
Aberrant Phosphorylation of SMAD4 Thr277-Mediated USP9x-SMAD4 Interaction by Free Fatty Acids Promotes Breast Cancer Metastasis.
Article in Cancer research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 49 citations in OpenAlex.
- Decoding triple negative breast cancer bone metastasis: from 3D bioprinted models to clinical translation.Journal of nanobiotechnology · 2026Review
- The deubiquitinase USP35: from an oncogenic hub to a therapeutic target in human cancers.Frontiers in oncology · 2026Review
- Research progress of DUB enzyme in breast cancer.Clinical and experimental medicine · 2025Review
- USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemness.Cell death & disease · 2025Article
- Oncogenic and immunological functions of USP35 in pan-cancer and its potential as a biomarker in kidney clear cell carcinoma.BMC cancer · 2025Article
- Ubiquitin-specific protease: an emerging key player in cardiomyopathy.Cell communication and signaling : CCS · 2025Review
- The deubiquitylating enzyme Fat facets promotes Fat signalling and restricts tissue growth.Nature communications · 2025Article
- Review
- Adipocytes promote metastasis of breast cancer by attenuating the FOXO1 effects and regulating copper homeostasis.Cancer cell international · 2024Article
- KDM5B promotes SMAD4 loss-driven drug resistance through activating DLG1/YAP to induce lipid accumulation in pancreatic ductal adenocarcinoma.Cell death discovery · 2024Article
- Roles of USP9X in cellular functions and tumorigenesis (Review).Oncology letters · 2023Review
- Deubiquitylating Enzymes in Cancer and Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Review
- Understanding the mechanisms underlying obesity in remodeling the breast tumor immune microenvironment: from the perspective of inflammation.Cancer biology & medicine · 2023Review
- Antifatigue effect of naringin on improving antioxidant capacity and mitochondrial function and preventing muscle damage.Experimental biology and medicine (Maywood, N.J.) · 2022Article
- Monoubiquitination in Homeostasis and Cancer.International journal of molecular sciences · 2022Review
- A Novel Metabolic Reprogramming Strategy for the Treatment of Diabetes-Associated Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- The role of ubiquitination and deubiquitination in tumor invasion and metastasis.International journal of biological sciences · 2022Review
- Aldehyde Dehydrogenase Isoform 1 Predicts a Poor Prognosis of Acute Cerebral Infarction.Contrast media & molecular imaging · 2022Article
- Roles and Mechanisms of Deubiquitinases (DUBs) in Breast Cancer Progression and Targeted Drug Discovery.Life (Basel, Switzerland) · 2021Review
- Correlation between loss of Smad4 and clinical parameters of non-small cell lung cancer: an observational cohort study.BMC pulmonary medicine · 2021Observational
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Obesity increases the risk of distant metastatic recurrence and reduces breast cancer survival. However, the mechanisms behind this pathology and identification of relevant therapeutic targets are poorly defined. Plasma free fatty acids (FFA) levels are elevated in obese individuals. Here we report that TGFβ transiently activates ERK and subsequently phosphorylates SMAD4 at Thr277, which facilitates a SMAD4-USP9x interaction, SMAD4 nuclear retention, and stimulates TGFβ/SMAD3-mediated transcription of Twist and Snail. USP9x inhibited the E3 ubiquitin-protein ligase TIF1γ from binding and monoubiquitinating SMAD4, hence maintaining the SMAD4 nuclear retention. FFA further facilitated TGFβ-induced ERK activation, SMAD4 phosphorylation, and nuclear retention, promoting TGFβ-dependent cancer progression. Inhibition of ERK and USP9x suppressed obesity-induced metastasis. In addition, clinical data indicated that phospho-ERK and -SMAD4 levels correlate with activated TGFβ signaling and metastasis in overweight/obese patient breast cancer specimens. Altogether, we demonstrate the vital interaction of USP9x and SMAD4 for governing TGFβ signaling and dyslipidemia-induced aberrant TGFβ activation during breast cancer metastasis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.